Ibrutinib induces multiple functional defects in the neutrophil response against Aspergillus fumigatus

• Published in: Haematologica (Roma) Vol. 105; no. 2; pp. 478 - 489
• Main Authors: Blez, Damien, Blaize, Marion, Soussain, Carole, Boissonnas, Alexandre, Meghraoui-Kheddar, Aïda, Menezes, Natacha, Portalier, Anaïs, Combadière, Christophe, Leblond, Véronique, Ghez, David, Fekkar, Arnaud
• Format: Journal Article
• Language: English
• Published: Italy Ferrata Storti Foundation 01.02.2020
• Subjects: Adenine - analogs & derivatives; Aspergillosis - drug therapy; Aspergillus fumigatus; Cancer; Hematology; Human health and pathology; Humans; Immunology; Life Sciences; Neutrophils; Pharmaceutical sciences; Pharmacology; Piperidines; Spores, Fungal
• ISSN: 0390-6078; 1592-8721; 1592-8721
• DOI: 10.3324/haematol.2019.219220

The Bruton tyrosine kinase inhibitor ibrutinib has become a leading therapy against chronic lymphoid leukemia. Recently, ibrutinib has been associated with the occurrence of invasive fungal infections, in particular invasive aspergillosis. The mechanisms underlying the increased susceptibility to fungal infections associated with exposure to ibrutinib are currently unknown. Innate immunity, in particular polymer-phonuclear neutrophils, represents the cornerstone of anti- immunity; however, the potential impact of ibrutinib on neutrophils has been little studied. Our study investigated the response to and neutrophil function in patients with chronic lymphoid leukemia or lymphoma, who were undergoing ibrutinib therapy. We studied the consequences of ibrutinib exposure on the functions and anti- responses of neutrophils obtained from healthy donors and 63 blood samples collected at different time points from 32 patients receiving ibrutinib for lymphoid malignancies. We used both flow cytometry and video-microscopy approaches to analyze neutrophils' cell surface molecule expression, cytokine production, oxidative burst, chemotaxis and killing activity against Ibrutinib is associated, both and in patients under treatment, with multiple functional defects in neutrophils, including decreased production of reactive oxygen species, impairment of their capacity to engulf and inability to efficiently kill germinating conidia. Our results demonstrate that ibrutinib-exposed neutrophils develop significant functional defects that impair their response against , providing a plausible explanation for the emergence of invasive aspergillosis in ibrutinib-treated patients.